Abstract 3682: Glutamine addiction of c-MAF overexpressing cells drives dysregulation of purine metabolism
Authors: Julia Sze Lynn Lim, Phyllis Shu Yun Chong, Wee-Joo Chng
Journal: Cancer Research (2023)

Abstract c-MAF, a bZIP transcription factor, is overexpressed as a consequence of t(14;16) translocation and represents a driver oncogene in this subtype. Clinically, patients with t(14;16) translocation constitute a high-risk group with adverse survival outcomes. Since transcription factors are not classical targets for the development of small molecule inhibitors, elucidating pathways downstream of c-MAF could present as potential therapeutic targets. Critically, gene expression profiling studies of c-MAF showed a class of recurrently deregulated metabolic genes. Hence, this warrants further studies into the underexplored role of metabolism and the deregulated metabolic pathways mediated by c-MAF. First, we confirmed that t(14;16) cells were dependent on c-MAF expression for cell viability. Abrogation of c-MAF deregulated sensitivity to glycolytic inhibitors and influenced metabolite readouts. Importantly, analysis of quantitative metabolic profile of c-MAF driven myeloma using metabolomics identified 41% (48/116) of metabolites to vary significantly. Classification of differential metabolites into metabolic pathways was performed using the software MetaboAnalyst 5.0 to elucidate a role of c-MAF in de novo purine metabolism. Despite an increased source of PRPP derived from the pentose phosphate pathway, we observed significant decrease in output of IMP (fold change=0.6, p=0.028). We postulate that this might result from lowered levels of some non-essential amino acids substrates needed by enzymes in the de novo purine biosynthesis pathway such as glutamine (fold change=0.08, p=0.155) and aspartate (fold change=0.3, p=0.022). Furthermore, GSEA from RNA-seq data performed by c-MAF loss-of-function studies identified ADCY1, ADCY5 and GALR3, suggesting a direct regulation of purine metabolic genes by c-MAF. Notably, to validate whether c-MAF displayed metabolic dependency on glutamine to drive purine biosynthesis, we performed nutrient starvation studies which showed glutamine dependency in c-MAF overexpressed cells. We also systematically knockdown glucose transporters (GLUT8 and GLUT4) or glutamine transporters (ASCT2 and SNAT1) and saw a greater dependency on glutamine transporters for cell viability. As a proof of concept, c-MAF overexpressed cells were more sensitive to purine depletion by LTX suggesting its dependency on purine metabolism. The downstream identification of biological association of c-MAF with cancer metabolism may emerge as a new therapeutic strategy for MM patients. Taken together, our study suggests that metabolic perturbations present as a likely key Achilles heel in MM, and could potentially shift the current treatment paradigm. Citation Format: Julia Sze Lynn Lim, Phyllis Shu Yun Chong, Wee-Joo Chng. Glutamine addiction of c-MAF overexpressing cells drives dysregulation of purine metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3682.